Second primary or contralateral breast cancer (CBC) is an issue of growing importance given that breast cancer incidence and survival rates are increasing. Treatment with tamoxifen decreases risk of CBC by 47 percent. However, it is only recommended for women with estrogen receptor-positive (ER+) breast cancer, as it has no effect on estrogen receptor-negative (ER-) tumors. Unfortunately, half of all ER+ first breast cancers fail to respond to tamoxifen, and most that do respond eventually develop tamoxifen resistance. Preliminary data suggest that tamoxifen users may develop more ER- CBC's than expected. Thus, one of our objectives is to test the hypothesis that tamoxifen use increases risk of ER- CBC. Additionally, while tamoxifen reduces a woman's risk of ER+ CBC, many women treated with tamoxifen nonetheless do develop it. Mechanisms by which tamoxifen inhibits the development of some ER+ CBC's, but not all, may be related to altered expression of ER or factors downstream of the ER resulting in altered interaction with tamoxifen in some tumors. Thus, a second objective of this study is to evaluate how tamoxifen affects the expression of selected tamoxifen resistance-associated factors. Findings related to these factors may point toward additional mechanisms by which resistance may unfold and improve our ability to tailor treatments. We propose to conduct a population-based nested case-control study of 400 women aged 40-79 who have been diagnosed with CBC and 800 matched controls diagnosed with a first but never a CBC. The specific questions to be evaluated are: (1) Does tamoxifen therapy for a first breast cancer influence risk of ER- and ER+ CBC? (2) How does tamoxifen therapy for a first breast cancer alter the expression of tumor markers involved in pathways leading to tamoxifen resistance in CBC? (3) Do the expression of these tumor markers by first breast cancers or other patient characteristics predict which women have increased or decreased risks of developing CBC if they use tamoxifen? (4) Among the CBC cases, how does tamoxifen alter the expression of these tumor markers in first compared to contralateral cancers?